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Bioorg Med Chem Lett. 2009 Nov 15;19(22):6307-12. doi: 10.1016/j.bmcl.2009.09.096. Epub 2009 Sep 27.

Discovery and optimization of potent and selective triazolopyridazine series of c-Met inhibitors.

Author information

1
Amgen Inc., One Kendall Square, Building 1000, Cambridge, MA 02139, USA; Amgen Inc., One Amgen Center Drive, Thousand Oaks, CA 91320, USA. aboezio@amgen.com

Erratum in

  • Bioorg Med Chem Lett. 2010 Jan 15;20(2):773. Fang, Mei [added]; Qu, Yusheng [added].

Abstract

Deregulation of the receptor tyrosine kinase c-Met has been implicated in several human cancers and is an attractive target for small molecule drug discovery. We previously showed that O-linked triazolopyridazines can be potent inhibitors of c-Met. Herein, we report the discovery of a related series of N-linked triazolopyridazines which demonstrate nanomolar inhibition of c-Met kinase activity and display improved pharmacodynamic profiles. Specifically, the potent time-dependent inhibition of cytochrome P450 associated with the O-linked triazolopyridazines has been eliminated within this novel series of inhibitors. N-linked triazolopyridazine 24 exhibited favorable pharmacokinetics and displayed potent inhibition of HGF-mediated c-Met phosphorylation in a mouse liver PD model. Once-daily oral administration of 24 for 22days showed significant tumor growth inhibition in an NIH-3T3/TPR-Met xenograft mouse efficacy model.

PMID:
19819693
DOI:
10.1016/j.bmcl.2009.09.096
[Indexed for MEDLINE]

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